L-BLP25 Vaccine plus Letrozole Induces a TH1 Immune Response and has Additive Antitumor Activity in MUC-1 Expressing Mammary Tumors in Mice

Activating the host immune system for therapeutic benefit has long been a goal in cancer immunotherapy. Human mucin1 (hMUC1) glycoprotein is a tumor-associated antigen (TAA) overexpressed in 90% of human adenocarcinomas, including those of breast and lung. Stimuvax® (L-BLP25) is an innovative cancer vaccine designed to induce an immune response against cancer cells that overexpress MUC1. The very low toxicity profile of L-BLP25 renders it amenable to combination therapies without the concern of compounding toxicities. Therefore, clinical studies evaluating the benefits of L-BLP25 immunotherapy combined with breast cancer adjuvant hormonal therapies are being considered. Hormonal therapies have demonstrated immunomodulatory effects that may interfere with the L-BLP25-induced immune response. Therefore, the immunomodulatory effects of hormonal therapy on the L-BLP25-induced immune response were evaluated in the following preclinical studies: (1) a study of hormonal therapy, ospemifene, on the development and growth of estrogen receptor positive mammary tumors in the polyomavirus middle-T transgenic (MTag.Tg) mouse model of breast cancer; and (2) a study of L-BLP25 in combination with hormonal therapy (tamoxifen, letrozole) in a double transgenic human-MUC1 expressing mammary tumor (hMUC1.Tg, MTag.Tg) mouse model of breast cancer.;Immunomodulatory strategies such as certain cytotoxic drugs are used to modify immune responses in cancer patients. In L-BLP25 clinical trials, a low, intravenous dose of cyclophosphamide is administered three days prior to immunotherapy to suppress T-suppressor cells. Although the dose used in this setting is below the cytotoxic dose, it is unknown whether any of the observed antitumor effects following L-BLP25 therapy can be attributed to the immunomodulatory effects of cyclophosphamide. Therefore, a third study was conducted in order to determine the effects of combining L-BLP25 immunotherapy with low-dose cyclophosphamide, and for evaluating the antitumor effects of low versus cytotoxic doses of cyclophosphamide.;The results of the work presented in this dissertation show: 1) ospemifene increased survival and exerted an antitumor effect on the development and growth of estrogen receptor positive mammary tumors in the MTag.Tg mouse model, demonstrating estrogen responsiveness of the model; 2) hormonal therapy and L-BLP25 combination studies showed that hormonal therapy does not interfere with the L-BLP25 induced predominant Th1 response, and the combination of L-BLP25 with the aromatase inhibitor letrozole has additive antitumor activity; and 3) pretreatment with low-dose cyclophosphamide potentiated the L-BLP25 induced Th1 cytokine response in addition to producing a modest antitumor response.;In summary, these results suggest that L-BLP25 alone or in combination with hormonal therapy is an effective new strategy for breast cancer prevention and treatment, and low-dose cyclophosphamide pretreatment potentiates the immune response to the vaccine. Stimuvax® (L-BLP25) appears to be a promising new immunotherapy for targeting various hMUC1-expressing adenocarcinomas.